Hepatic stem cells and their progeny (e.g., hepatoblasts and committed progenitors) have considerable expansion potential. For this reason, these cell populations are desirable candidates for cell therapies, including bioartificial livers or cell transplantation. Despite this promise, however, the full potential of liver cell therapy remains to be realized.
The in vitro propagation of hepatic stem cells and their progeny has proven to be challenging, in part, because in vitro culture conditions are not always optimal for transition from the laboratory bench to the clinic. For example, some culture conditions are not good for survival, can greatly retard cell division, or can promote cell differentiation towards undesired fates. As well, some culture conditions require the addition of factors (e.g., serum) that can introduce contaminants and thereby limit their application in treating humans.
Maintenance of normal cells, especially progenitors, requires feeders of mesenchymal companion cells, known to provide paracrine signals critical for survival and function of the progenitors. There is a need to identify categories of mesenchymal cell feeders and then to use them as models to identify their paracrine signals, extracellular matrix components and soluble signals, that mediate expansion, lineage restriction towards specific fates, or differentiation of hepatic progenitors towards their adult fates of biliary epithelia and hepatocytes. Defining the signals enables one to use the signals on their own in the proper combinations and without the feeders to elicit the desired biological responses from the hepatic progenitors and that includes survival, expansion, lineage restriction towards a fate, and full differentiation to mature liver cells. Thus, there is a need for culture conditions that are defined so as to obviate the heretofore requirement of feeder cells.